Golden Hour Intravenous Thrombolysis for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

OBJECTIVES: The benefits of intravenous thrombolysis are time-dependent, with maximum efficacy when administered within the first "golden" hour after onset. Nevertheless, the impact of golden hour thrombolysis has not been well quantified. METHODS: Medline, Embase, and Web of Science databases were systematically searched from inception to August 27, 2023. We included studies that reported safety and efficacy outcomes of ischemic stroke patients treated with intravenous thrombolysis in the golden hour versus later treatment window. The primary outcome was an excellent functional outcome, defined as a modified Rankin Scale score of 0-1 at 90 days. The secondary efficacy outcome was a good functional outcome (defined as modified Rankin Scale score of 0-2). The main safety outcome was symptomatic intracerebral hemorrhage. RESULTS: Seven studies involving 78,826 patients met the selection criteria. Golden hour thrombolysis was associated with higher odds of 90-day excellent functional outcomes (OR 1.40, 95% CI 1.16-1.67) and 90-day good functional outcomes (OR 1.38, 95% CI 1.13-1.69) compared with thrombolysis outside the golden hour. The number needed to treat to benefit for golden hour thrombolysis to reduce disability by at least 1 level on the modified Rankin Scale per patient was 2.6. Rates of symptomatic intracerebral hemorrhage and mortality were similar between groups. INTERPRETATION: Golden hour thrombolysis significantly improved acute ischemic stroke outcomes. The findings provide rationale for intensive efforts aimed at expediting thrombolytic therapy within the golden hour window following the onset of acute ischemic stroke. ANN NEUROL 2024.

Integer factorization using stochastic magnetic tunnel junctions.

Conventional computers operate deterministically using strings of zeros and ones called bits to represent information in binary code. Despite the evolution of conventional computers into sophisticated machines, there are many classes of problems that they cannot efficiently address, including inference, invertible logic, sampling and optimization, leading to considerable interest in alternative computing schemes. Quantum computing, which uses qubits to represent a superposition of 0 and 1, is expected to perform these tasks efficiently1-3. However, decoherence and the current requirement for cryogenic operation4, as well as the limited many-body interactions that can be implemented, pose considerable challenges. Probabilistic computing1,5-7 is another unconventional computation scheme that shares similar concepts with quantum computing but is not limited by the above challenges. The key role is played by a probabilistic bit (a p-bit)-a robust, classical entity fluctuating in time between 0 and 1, which interacts with other p-bits in the same system using principles inspired by neural networks8. Here we present a proof-of-concept experiment for probabilistic computing using spintronics technology, and demonstrate integer factorization, an illustrative example of the optimization class of problems addressed by adiabatic9 and gated2 quantum computing. Nanoscale magnetic tunnel junctions showing stochastic behaviour are developed by modifying market-ready magnetoresistive random-access memory technology10,11 and are used to implement three-terminal p-bits that operate at room temperature. The p-bits are electrically connected to form a functional asynchronous network, to which a modified adiabatic quantum computing algorithm that implements three- and four-body interactions is applied. Factorization of integers up to 945 is demonstrated with this rudimentary asynchronous probabilistic computer using eight correlated p-bits, and the results show good agreement with theoretical predictions, thus providing a potentially scalable hardware approach to the difficult problems of optimization and sampling.

Retraction Note: A homing system targets therapeutic T cells to brain cancer.

This Article has been retracted; see accompanying Retraction.

First Measurement Using Elliptically Polarized Photons of the Double-Polarization Observable E for γp→pπ

We report the measurement of the helicity asymmetry E for the pπ^{0} and nπ^{+} final states using, for the first time, an elliptically polarized photon beam in combination with a longitudinally polarized target at the Crystal Ball experiment at MAMI. The results agree very well with data that were taken with a circularly polarized photon beam, showing that it is possible to simultaneously measure polarization observables that require linearly (e.g., G) and circularly polarized photons (e.g., E) and a longitudinally polarized target. The new data cover a photon energy range 270-1400 MeV for the pπ^{0} final state (230-842 MeV for the nπ^{+} final state) and the full range of pion polar angles, θ, providing the most precise measurement of the observable E. A moment analysis gives a clear observation of the pη cusp in the pπ^{0} final state.

A homing system targets therapeutic T cells to brain cancer.

Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.

Progressive multifocal leukoencephalopathy in patients with chronic kidney disease.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system infection caused by the human polyomavirus 2, leading to demyelination from oligodendrocyte death and rapid neurologic decline. Most commonly, PML affects patients in immunocompromised states. However, rare reports of PML in an immunocompetent host exist. Here, we report two cases of PML in older individuals with chronic kidney disease (CKD). CKD can ultimately lead to immune system dysfunction and place patients in a relatively immunosuppressed state. Testing for JC virus should remain a consideration for rapid, unexplained neurologic decline even without known immunocompromised status in the appropriate clinical setting.

Capture and metabolomic analysis of the human endometrial epithelial organoid secretome.

Suboptimal uterine fluid (UF) composition can lead to pregnancy loss and likely contributes to offspring susceptibility to chronic adult-onset disorders. However, our understanding of the biochemical composition and mechanisms underpinning UF formation and regulation remain elusive, particularly in humans. To address this challenge, we developed a high-throughput method for intraorganoid fluid (IOF) isolation from human endometrial epithelial organoids. The IOF is biochemically distinct to the extraorganoid fluid (EOF) and cell culture medium as evidenced by the exclusive presence of 17 metabolites in IOF. Similarly, 69 metabolites were unique to EOF, showing asymmetrical apical and basolateral secretion by the in vitro endometrial epithelium, in a manner resembling that observed in vivo. Contrasting the quantitative metabolomic profiles of IOF and EOF revealed donor-specific biochemical signatures of organoids. Subsequent RNA sequencing of these organoids from which IOF and EOF were derived established the capacity to readily perform organoid multiomics in tandem, and suggests that transcriptomic regulation underpins the observed secretory asymmetry. In summary, these data provided by modeling uterine luminal and basolateral fluid formation in vitro offer scope to better understand UF composition and regulation with potential impacts on female fertility and offspring well-being.

Periostin's role in uterine leiomyoma development: a mini-review on the potential periostin poses as a pharmacological intervention for uterine leiomyoma.

Uterine leiomyomas, also known as fibroids or myomas, occur in an estimated 70-80% of reproductive aged women. Many experience debilitating symptoms including pelvic pain, abnormal uterine bleeding (AUB), dyspareunia, dysmenorrhea, and infertility. Current treatment options are limited in preserving fertility, with many opting for sterilizing hysterectomy as a form of treatment. Currently, surgical interventions include hysterectomy, myomectomy, and uterine artery embolization in addition to endometrial ablation to control AUB. Non-surgical hormonal interventions, including GnRH agonists, are connotated with negative side effects and are unacceptable for women desiring fertility. Periostin, a regulatory extra cellular matrix (ECM) protein, has been found to be expressed in various gynecological diseases including leiomyomas. We previously determined that periostin over-expression in immortalized myometrial cells led to the development of a leiomyoma-like cellular phenotype. Periostin is induced by TGF-ß, signals through the PI3K/AKT pathway, induces collagen production, and mediates wound repair and fibrosis, all of which are implicated in leiomyoma pathology. Periostin has been linked to other gynecological diseases including ovarian cancer and endometriosis and is being investigated as pharmacological target for treating ovarian cancer, post-surgical scarring, and numerous other fibrotic conditions. In this review, we provide discussion linking pathological inflammation and wound repair, with a TGF-ß-periostin-collagen signaling in the pathogenesis of leiomyomas, and ultimately the potential of periostin as a druggable target to treat leiomyomas.

Effect of Salvadora persica on resin-dentin bond stability.

BACKGROUND: The stability of resin-dentin interfaces is still highly questionable. The aim of this study was to evaluate the effect of Salvadora persica on resin-dentin bond durability. MATERIALS AND METHODS: Extracted human third molars were used to provide mid-coronal dentin, which was treated with 20% Salvadora persica extract for 1 min after acid-etching. Microtensile bond strength and interfacial nanoleakage were evaluated after 24 h and 6 months. A three-point flexure test was used to measure the stiffness of completely demineralized dentin sticks before and after treatment with Salvadora persica extract. The hydroxyproline release test was also used to measure collagen degradation by endogenous dentin proteases. Statistical analysis was performed using two-way ANOVA followed by post hoc Bonferroni test and unpaired t-test. P-values < 0.05 were considered statistically significant. RESULTS: The use of Salvadora persica as an additional primer with etch-and-rinse adhesive did not affect the immediate bond strengths and nanoleakage (p > 0.05). After 6 months, the bond strength of the control group decreased (p = 0.007), and nanoleakage increased (p = 0.006), while Salvadora persica group showed no significant difference in bond strength and nanoleakage compared to their 24 h groups (p > 0.05). Salvadora persica increased dentin stiffness and decreased collagen degradation (p < 0.001) compared to their controls. CONCLUSION: Salvadora persica extract pretreatment of acid-etched dentin preserved resin-dentin bonded interface for 6 months. CLINICAL SIGNIFICANCE: Durability of resin-dentin bonded interfaces is still highly questionable. Endogenous dentinal matrix metalloproteinases play an important role in degradation of dentinal collagen within such interfaces. Salvadora persica may preserve resin-dentin interfaces for longer periods of time contributing to greater clinical success and longevity of resin composite restorations.

Detecting white spot lesions on post-orthodontic oral photographs using deep learning based on the YOLOv5x algorithm: a pilot study.

BACKGROUND: Deep learning model trained on a large image dataset, can be used to detect and discriminate targets with similar but not identical appearances. The aim of this study is to evaluate the post-training performance of the CNN-based YOLOv5x algorithm in the detection of white spot lesions in post-orthodontic oral photographs using the limited data available and to make a preliminary study for fully automated models that can be clinically integrated in the future. METHODS: A total of 435 images in JPG format were uploaded into the CranioCatch labeling software and labeled white spot lesions. The labeled images were resized to 640 × 320 while maintaining their aspect ratio before model training. The labeled images were randomly divided into three groups (Training:349 images (1589 labels), Validation:43 images (181 labels), Test:43 images (215 labels)). YOLOv5x algorithm was used to perform deep learning. The segmentation performance of the tested model was visualized and analyzed using ROC analysis and a confusion matrix. True Positive (TP), False Positive (FP), and False Negative (FN) values were determined. RESULTS: Among the test group images, there were 133 TPs, 36 FPs, and 82 FNs. The model's performance metrics include precision, recall, and F1 score values of detecting white spot lesions were 0.786, 0.618, and 0.692. The AUC value obtained from the ROC analysis was 0.712. The mAP value obtained from the Precision-Recall curve graph was 0.425. CONCLUSIONS: The model's accuracy and sensitivity in detecting white spot lesions remained lower than expected for practical application, but is a promising and acceptable detection rate compared to previous study. The current study provides a preliminary insight to further improved by increasing the dataset for training, and applying modifications to the deep learning algorithm. CLINICAL REVELANCE: Deep learning systems can help clinicians to distinguish white spot lesions that may be missed during visual inspection.

Treatment with onion bulb extract both prevents and reverses allergic inflammation in a murine model of asthma.

CONTEXT: Asthma presents a global health challenge. The main pharmacotherapy is synthetic chemicals and biological-based drugs that are costly, and have significant side effects. In contrast, use of natural products, such as onion (Allium cepa L., Amaryllidaceae) in the treatment of airway diseases has increased world-wide because of their perceived efficacy and little safety concerns. However, their pharmacological actions remain largely uncharacterized. OBJECTIVE: We investigated whether onion bulb extract (OBE) can (1) reverse established asthma phenotype (therapeutic treatment) and/or (2) prevent the development of the asthma phenotype, if given before the immunization process (preventative treatment). MATERIALS AND METHODS: Six groups of male Balb/c mice were established for the therapeutic (21 days) and five groups for the preventative (19 days) treatment protocols; including PBS and house dust mite (HDM)-challenged mice treated with vehicle or OBE (30, 60, and 100 mg/kg/i.p.). Airways inflammation was determined using cytology, histology, immunofluorescence, Western blot, and serum IgE. RESULTS: Therapeutic (60 mg/kg/i.p.) and preventative (100 mg/kg/i.p.) OBE treatment resulted in down-regulation of HDM-induced airway cellular influx, histopathological changes and the increase in expression of pro-inflammatory signaling pathway EGFR, ERK1/2, AKT, pro-inflammatory cytokines and serum IgE. DISCUSSION AND CONCLUSION: Our data show that OBE is an effective anti-inflammatory agent with both therapeutic and preventative anti-asthma effects. These findings imply that onion/OBE may be used as an adjunct therapeutic agent in established asthma and/or to prevent development of allergic asthma. However, further studies to identify the active constituents, and demonstrate proof-of-concept in humans are needed.

The effect of inhibiting hindbrain A2 noradrenergic neurons by 6-Hydroxydopamine on lipopolysaccharide-treated male rats autistic animal model.

Autism spectrum disorder (ASD) is a complex neurodevelopmental illness that often emerges in early childhood. The incidence of ASD has shown a notable rise in recent years. ASD is defined by deficits in social communication, and presence of rigid and repetitive behaviors and interests. The underlying mechanisms of ASD remain elusive. Multiple studies have documented the presence of neuroinflammation and increased levels of inflammatory cytokines, specifically, IL-6, TNF, and NF-κB, in various brain regions, including the prefrontal cortex (PFC) and hippocampus in individuals with ASD. Noradrenergic neurons play a crucial role in brain development and the regulation of motor, behavioral, and memory functions. This study sought to examine the impact of intracerebroventricular (icv.) injection of the neurotoxin, 6-hydroxydopamine (6-OHDA), in the caudal dorsal vagal complex A2 neurons on various neuroinflammatory pathways at the hippocampus and PFC in valproic acid (VPA) autistic animal model. This was done in conjunction with an intraperitoneal (i.p.) injection of Lipopolysaccharides (LPS) in animal models with VPA-induced autism. We specifically examined the impact of the caudal fourth ventricle 6-OHDA icv. injection and LPS (i.p.) injection on self-grooming behavior. We measured the mRNA expression of IL-6, TNF-a, and NF-κB using qRT-PCR, and the protein expression of COX-2, GPX-1, p-AMPK, and AMPK using western blot analysis. The self-grooming activity was considerably higher in the combined treatment group (6-OHDA icv. + LPS i.p.) compared to the control group. A substantial increase observed in the expression of IL-6, TNF-α, and NF-κB genes in the PFC of the treatment group that received icv. Administration of 6-OHDA, compared to the control group. The VPA-autism rats that received the combo treatment exhibited a slight increase in the expression level of NF-κB gene in the hippocampus, compared to the control group. At the PFC, we noticed a substantial drop in the expression of the antioxidant protein GPX-1 in the group that received the combo treatment compared to the control group. Our data investigates a novel aspect that the 6-OHDA-induced inhibition of hindbrain A2 neurons could be influencing the neuroinflammatory pathways in the PFC and hippocampus of autistic animal models.

Light-Activated Assembly of Connexon Nanopores in Synthetic Cells.

During developmental processes and wound healing, activation of living cells occurs with spatiotemporal precision and leads to rapid release of soluble molecular signals, allowing communication and coordination between neighbors. Nonliving systems capable of similar responsive release hold great promise for information transfer in materials and site-specific drug delivery. One nonliving system that offers a tunable platform for programming release is synthetic cells. Encased in a lipid bilayer structure, synthetic cells can be outfitted with molecular conduits that span the bilayer and lead to material exchange. While previous work expressing membrane pore proteins in synthetic cells demonstrated content exchange, user-defined control over release has remained elusive. In mammalian cells, connexon nanopore structures drive content release and have garnered significant interest since they can direct material exchange through intercellular contacts. Here, we focus on connexon nanopores and present activated release of material from synthetic cells in a light-sensitive fashion. To do this, we re-engineer connexon nanopores to assemble after post-translational processing by a protease. By encapsulating proteases in light-sensitive liposomes, we show that assembly of nanopores can be triggered by illumination, resulting in rapid release of molecules encapsulated within synthetic cells. Controlling connexon nanopore activity provides an opportunity for initiating communication with extracellular signals and for transferring molecular agents to the cytoplasm of living cells in a rapid, light-guided manner.

Sire modulates developmental kinetics and transcriptome of the bovine embryo.

In brief: The first week of gestation is a period of major pregnancy loss in cattle, this study reveals that the male plays a key role in regulating embryonic development during this time. Abstract: The impact of sire on preimplantation embryonic development in cattle remains poorly understood. This study evaluated differences in embryos produced in vitro from sires with varying capacities to produce blastocysts. Sires classified as high (HP) and low performing (LP) based on their ability to produce embryos were used to better understand how sire regulates embryonic development. By monitoring development, it was determined that the most common arrest stage was the five- to six-cell stage. Embryos (four to six cells) from HP and LP sires were then analyzed for autophagic activity, where embryos for LP sires exhibited increased autophagy than HP-derived embryos. Transcriptome analysis of four-cell embryos found that embryos from LP sires might have issues in sperm mitochondrial clearance, histone retention, and DNA damage, while HP sires had increased expression of genes involved in transcription, chromosome segregation, and cell division. In conclusion, LP sires had an increased proportion of embryos arresting at the five- to six-cell stage, and these embryos had higher rates of cellular stress due to paternal contributions from the spermatozoon.

First Evidence of Axial Shape Asymmetry and Configuration Coexistence in

The excited states of N=44 ^{74}Zn were investigated via γ-ray spectroscopy following ^{74}Cu ß decay. By exploiting γ-γ angular correlation analysis, the 2_{2}^{+}, 3_{1}^{+}, 0_{2}^{+}, and 2_{3}^{+} states in ^{74}Zn were firmly established. The γ-ray branching and E2/M1 mixing ratios for transitions deexciting the 2_{2}^{+}, 3_{1}^{+}, and 2_{3}^{+} states were measured, allowing for the extraction of relative B(E2) values. In particular, the 2_{3}^{+}→0_{2}^{+} and 2_{3}^{+}→4_{1}^{+} transitions were observed for the first time. The results show excellent agreement with new microscopic large-scale shell-model calculations, and are discussed in terms of underlying shapes, as well as the role of neutron excitations across the N=40 gap. Enhanced axial shape asymmetry (triaxiality) is suggested to characterize ^{74}Zn in its ground state. Furthermore, an excited K=0 band with a significantly larger softness in its shape is identified. A shore of the N=40 "island of inversion" appears to manifest above Z=26, previously thought as its northern limit in the chart of the nuclides.

Comparative outcomes among inlay grafted incised plate, onlay preputial flap and tubularized incised plate urethroplasty for the repair of distal penile hypospadias with a narrow urethral plate.

PURPOSE: We conducted this study, comparing the outcomes among Transverse Onlay Island Flap, inlay grafted incised plate and our previous records of tubularized incised plate urethroplasty (TIPU) in patients with narrow urethral plates, aiming to determine which method of repair provides a good outcome. METHODS: This hybrid study included two datasets. The first from a prospective randomized study evaluating outcomes of two treatment modalities; Inlay graft and only flap for distal hypospadias with shallow urethral plate with 80 patients (40 patients in each group) included, the second based on our previous records of TIPU in 40 patients with distal primary hypospadias with narrow urethral plate. RESULTS: The success rate in inlay graft urethroplasty group (n = 40) was 87.5%; glandular dehiscence occurred in one case (2.5%), fistulas occurred in 2 cases (5%), and narrow meatus occurred in two cases (5%). Success rate in onlay flap urethroplasty group (n = 40) was 82.5%; glandular dehiscence occurred in two cases (5%), fistulas occurred in two cases (5%), and narrow meatus occurred in three cases (7.5%). TIPU group (n = 40) had success rate of 62.5%; glandular dehiscence occurred in eight cases (20%), fistulas occurred in five cases (12.5%), and narrow meatus occurred in seven cases (17.5%), with five cases exhibiting both narrow meatus with fistula. CONCLUSION: Inlay graft and onlay flap urethroplasty for repair of distal penile hypospadias with narrow urethral plate had higher success rate and fewer complications than traditional TIPU. Moreover, operative time was shorter in TIPU.

UPLC/ESI/MS profiling of red algae Galaxaura rugosa extracts and its activity against malaria mosquito vector, Anopheles pharoensis, with reference to Danio rerio and Daphnia magna as bioindicators.

BACKGROUND: Anopheles pharoensis has a major role in transmitting several human diseases, especially malaria, in Egypt?. Controlling Anopheles is considered as an effective strategy to eliminate the spread of malaria worldwide. Galaxaura rugosa is a species of red algae found in tropical to subtropical marine environments. The presence of G. rugosa is indicative of the ecosystem's overall health. The current work aims to investigate UPLC/ESI/MS profile of G. rugosa methanol and petroleum ether extracts and its activity against An. pharoensis and non-target organisms, Danio rerio and Daphnia magna. METHODS: Galaxaura rugosa specimens have been identified using DNA barcoding for the COI gene and verified as G. rugosa. The UPLC/ESI/MS profiling of G. rugosa collected from Egypt was described. The larvicidal and repellent activities of G. rugosa methanol and petroleum ether extracts against An. pharoensis were evaluated, as well as the toxicity of tested extracts on non-target organisms, Dan. rerio and Dap. magna. RESULTS: The UPLC/ESI/MS analysis of methanol and petroleum ether extracts led to the tentative identification of 57 compounds belonging to different phytochemical classes, including flavonoids, tannins, phenolic acids, phenyl propanoids. Larval mortality was recorded at 93.33% and 90.67% at 80 and 35 ppm of methanol and petroleum ether extracts, respectively, while pupal mortality recorded 44.44 and 22.48% at 35 and 30 ppm, respectively. Larval duration was recorded at 5.31 and 5.64 days by methanol and petroleum ether extracts at 80 and 35 ppm, respectively. A decrease in acetylcholinesterase (AChE) level and a promotion in Glutathione-S-transferase (GST) level of An. pharoensis 3rd instar larvae were recorded by tested extracts. The petroleum ether extract was more effective against An. pharoensis starved females than methanol extract. Also, tested extracts recorded LC50 of 1988.8, 1365.1, and 11.65, 14.36 µg/mL against Dan. rerio, and Dap. magna, respectively. CONCLUSIONS: Using red algae derivatives in An. pharoensis control could reduce costs and environmental impact and be harmless to humans and other non-target organisms.

A Computational First Principle Examination of the Elastic, Optical, Structural and Electronic Properties of AlRF3 (R = N, P) Fluoroperovskites Compounds.

This work describes an ab initio principle computational examination of the optical, structural, elastic, electronic and mechanical characteristics of aluminum-based compounds AlRF3 (R = N, P) halide-perovskites. For optimization purposes, we used the Birch-Murnaghan equation of state and discovered that the compounds AlNF3 and AlPF3 are both structurally stable. The IRelast software was used to compute elastic constants (ECs) of the elastic properties. The aforementioned compounds are stable mechanically. They exhibit strong resistance to plastic strain, possess ductile nature and anisotropic behavior and are scratch-resistant. The modified Becke-Johnson (Tb-mBJ) approximation was adopted to compute various physical properties, revealing that AlNF3 and AlPF3 are both metals in nature. From the density of states, the support of various electronic states in the band structures are explained. Other various optical characteristics have been calculated from the investigations of the band gap energy of the aforementioned compounds. These compounds absorb a significant amount of energy at high levels. At low energy levels, the compound AlNF3 is transparent to incoming photons, whereas the compound AlPF3 is somewhat opaque. The examination of the visual details led us to the deduction that the compounds AlNF3 and AlPF3 may be used in making ultraviolet devices based on high frequency. This computational effort is being made for the first time in order to investigate the aforementioned properties of these chemicals, which have yet to be confirmed experimentally.

Augmented antitumor effects of erlotinib and cabozantinib on A549 non-small cell lung cancer: In vitro and in vivo studies.

Non-small cell lung carcinoma is a challenging disease worldwide. This study aims to determine whether combining erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, with cabozantinib, a mesenchymal-epithelial transition factor (c-Met) inhibitor, would have an augmented therapeutic benefit on A549 cells. The combination of erlotinib and cabozantinib (5 µM) inhibited A549 cell viability compared to each monotherapy at ≥ 10 µM as confirmed by the MTT assay. Combination therapy also has a more potent inhibition of cellular migration than monotherapy using the wound-healing assay. Furthermore, mRNA expression analyses for assessing apoptosis, metastasis, and cell cycle-related genes, the results showed that combination therapy significantly inhibits levels of BCL-2, MMP-9, VEGF, and TGF-ß while inducing p53, p21, and BAX expression. In terms of oncogenic markers, western blotting analysis showed a significant reduction of BCl-2 expression and elevation in caspase3, p53, and p21 proteins as indicators of cell death via apoptosis. The antitumor in vivo effect of the combination therapy showed significant tumor inhibition compared to monotherapy. In conclusion, combination therapy could be a potential promising strategy to treat non-small cell lung carcinoma.

Protective role of Dodonaea viscosa extract against streptozotocin-induced hepatotoxicity and nephrotoxicity in rats.

Previous investigations have shown that D. viscosa herbal extract is often used to treat a variety of diseases. Therefore, the purpose of this study was to investigate any additional potential impacts on rat liver and kidney damage induced by diabetes. Streptozotocin (STZ) (60 mg/kg/day) was given as a single dosage to cause type 1 diabetes. After then, diabetic rats received oral doses of D. viscosa for four weeks at 150 and 300 mg/kg/day. Blood, liver, and kidney tissues were collected at the end of the treatment and examined. Analysis was made of the serum lipid profile, liver, and kidney functions, as well as blood biochemistry. Moreover, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), prostaglandin E-2 (PGE-2), and nitric oxide (NO) were estimated in serum. In liver and kidney samples, thiobarbituric acid reactive substances (TBARs) and reduced glutathione (GSH), as well as the pro-inflammatory cytokines and enzymatic activities of glutathione peroxidase (GPx), glutathione reeducates (GR), glutathione-S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) were analyzed. Histological changes in liver and kidney cross-sections were also observed. Our findings demonstrated that D. viscosa dramatically decreased pro-inflammatory indicators in blood, kidney, and liver tissues as well as blood glucose, and restored insulin levels, and lipid profiles. Additionally, it significantly raises the antioxidant enzyme activity SOD, CAT, GPx, and GST, while significantly lowering TBARs levels. The above-mentioned biochemical changes that took place in tissues were further supported by histological alterations. These findings imply that D. viscosa protects against STZ-induced hyperglycemia, aberrant lipid synthesis, and oxidative stress and that these benefits may be mediated by interacting with various targets to increase the levels of antioxidant enzymes in the liver and kidneys. Its mode of action and safety for use as medicine against various metabolic problems caused by diabetes require more research.